rs539283387

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.11G>C(p.Arg4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,333,304 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 26 hom., cov: 31)

Exomes 𝑓: 0.00099 ( 18 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.41

Publications

0 publications found

Variant links:

Genes affected

AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

AGRN Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AGRN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_198576.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018983781).

BP6

Variant 1-1020183-G-C is Benign according to our data. Variant chr1-1020183-G-C is described in ClinVar as Benign. ClinVar VariationId is 387476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1806/150780) while in subpopulation AFR AF = 0.0419 (1731/41268). AF 95% confidence interval is 0.0403. There are 26 homozygotes in GnomAd4. There are 859 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.11G>C	p.Arg4Pro	missense	Exon 1 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.11G>C	p.Arg4Pro	missense	Exon 1 of 39	NP_001292204.1	O00468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.11G>C	p.Arg4Pro	missense	Exon 1 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000620552.4	TSL:5	c.-404G>C		5_prime_UTR	Exon 1 of 39	ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1806

AN:

150674

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0421

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00317

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00871

GnomAD2 exomes

AF:

0.000944

AC:

AN:

26472

AF XY:

0.000552

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000985

Gnomad OTH exome

AF:

0.00232

GnomAD4 exome

AF:

0.000994

AC:

1176

AN:

1182524

Hom.:

Cov.:

AF XY:

0.000842

AC XY:

487

AN XY:

578112

show subpopulations

African (AFR)

AF:

0.0427

AC:

997

AN:

23362

American (AMR)

AF:

0.00275

AC:

AN:

12742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16880

East Asian (EAS)

AF:

0.0000393

AC:

AN:

25420

South Asian (SAS)

AF:

0.0000418

AC:

AN:

47866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27436

Middle Eastern (MID)

AF:

0.00216

AC:

AN:

3236

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

978096

Other (OTH)

AF:

0.00204

AC:

AN:

47486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0120

AC:

1806

AN:

150780

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

859

AN XY:

73662

show subpopulations

African (AFR)

AF:

0.0419

AC:

1731

AN:

41268

American (AMR)

AF:

0.00316

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67444

Other (OTH)

AF:

0.00862

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

176

265

353

441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00232

Hom.:

Asia WGS

AF:

0.00118

AC:

AN:

3410

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

AGRN-related disorder (1)

Congenital myasthenic syndrome 8 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.21

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.30

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

PhyloP100

-1.4

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.27

REVEL

Benign

0.13

Sift

Benign

0.26

Sift4G

Benign

0.30

PromoterAI

0.0041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.36

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over